Erythropoietin is essential for bone marrow erythropoiesis and erythropoietin receptor on non-erythroid cells including bone marrow stromal cells suggests systemic effects of erythropoietin. Recombinant erythropoietin administration is used predominantly in the dialysis clinic to treat anemia due to low endogenous erythropoietin production in end stage renal disease. Identification of non-hematopoietic response to erythropoietin in animal models may provide insight on potential off-target effects associated with long term erythropoietin therapy. Transgenic mice over-expressing erythropoietin have high hematocrit, reduced trabecular and cortical bone and bone marrow adipocytes. These mice also exhibit decreased bone morphogenic protein 2 driven ectopic bone and adipocyte formation. Erythropoietin treatment (1200 IU/kg) for ten days similarly exhibit increased hematocrit, reduced bone and bone marrow adipocytes without increased osteoclasts. Erythropoietin treatment also reduced bone morphogenic protein signaling in bone marrow. Interestingly, endogenous erythropoietin is required for normal differentiation of bone marrow stromal cells to osteoblasts and bone marrow adipocytes. In mice with erythropoietin receptor restricted to erythroid tissue, trabecular bone development is reduced with an increase in bone marrow adipocytes. These mice also exhibit decreased bone morphogenic protein 2 driven ectopic bone formation. When these mice were treated with erythropoietin, the expected increase in hematocrit was observed without reduced bone, suggesting that bone reduction with erythropoietin treatment is associated with non-erythropoietic erythropoietin response. Bone marrow stromal cells were harvested from these mouse models and transplanted into immunodeficient mice to assess development into a bone/marrow organ. As observed for endogenous bone formation in transgenic mice expressing high erythropoietin, the respective bone marrow cells transplanted into immunodeficient mice exhibited reduced differentiation to bone and adipocytes indicating that high erythropoietin inhibits osteogenesis and adipogenesis. Bone marrow stromal cells that lack erythropoietin receptor harvested from mice with erythropoietin receptor restricted to erythroid tissue showed ectopic bone formation with reduced trabecular regions and increase adipocytes compared with bone marrow stromal cells from control wild-type mice, indicating that loss of erythropoietin signaling favors adipogenesis at the expense of osteogenesis. In summary, endogenous erythropoietin signaling regulates bone marrow stromal cell fate and aberrant erythropoietin levels result in their impaired differentiation. These observations in animal models suggest that long-term erythropoietin therapy, may adversely affect bone health. The specific contribution of erythropoietin signaling in osteoblasts and adipocytes in determining bone marrow stromal cell fate will be investigated. Erythropoietin stimulated of nitric oxide production and protective activity to facilitate wound healing and recovery in skeletal muscle injury. We generated a myoglobin knock out mouse model to specifically assess the role of myoglobin in maintaining nitrate levels in skeletal muscle as a potential model to investigate erythropoietin response mediated via nitric oxide pathways. In rodents, skeletal muscle acts as a reservoir for nitrate mediated in part via nitric oxide reduction by oxymyoglobin and as a potential source for nitric oxide release, particularly during exercise. Loss of myoglobin decreases nitrate level in skeletal muscle which is further decreased by NOS inhibitor, L-NAME or during feeding of a low nitrite/nitrate diet. Mice with loss of myoglobin exhibit a compensatory increase in protein levels of xanthine oxidoreductase and sialin, that may contribute to maintenance of nitrite at levels comparable to control mice. Hence, myoglobin contributes significantly to maintaining the nitrate reservoir in skeletal muscle and loss of myoglobin activates compensatory mechanisms contributing to nitric oxide equilibrium. The interaction between nitric oxide pathways and erythropoietin metabolic response in skeletal muscle and their role in improved glucose tolerance be further investigated.